Metformin (originally sold as Glucophage) is an oral anti-diabetic drug. It is the first-line drug of choice for the treatment of type 2 diabetes, particularly in overweight and obese people and those with normal kidney function. Evidence is also mounting for its efficacy in gestational diabetes, although safety concerns still preclude its widespread use in this setting. It is also used in the treatment of polycystic ovary syndrome and has been investigated for other diseases where insulin resistance may be an important factor.

When prescribed appropriately, metformin causes few adverse effects—the most common is gastrointestinal upset—and, unlike many other anti-diabetic drugs, does not cause hypoglycemia if used alone. Lactic acidosis (a buildup of lactate in the blood) can be a serious concern in overdose and when it is prescribed to people with contraindications, but otherwise, there is no significant risk. Metformin helps reduce LDL cholesterol and triglyceride levels and is not associated with weight gain, and is the only anti-diabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes. As of 2009, metformin is one of only two oral anti-diabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide).

Pharmacokinetics

The exact mechanism of action of metformin is unclear but it appears to reduce glucose absorption from the GI tract, reduce gluconeogenesis and enhance insulin sensitivity by increasing peripheral glucose uptake and utilisation.

AbsorptionSlow and incomplete from the GI tract (oral); reduced if taken with food.

Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin HCL. In patients with advanced age, Metformin HCL should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Metformin HCL should not be titrated to the maximum dose.

Before initiation of Metformin HCL therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Metformin HCL discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or Metformin disposition—Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of Metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.Hypoxic statesCardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Metformin HCL therapy, the drug should be promptly discontinued.

Surgical proceduresMetformin HCL therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.Alcohol intakeAlcohol is known to potentiate the effect of Metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin HCL.

Impaired hepatic functionSince impaired hepatic function has been associated with some cases of lactic acidosis, Metformin HCL should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.HypoglycemiaHypoglycemia does not occur in patients receiving Metformin HCL alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.

Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Loss of control of blood glucose—When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Metformin HCL and temporarily administer insulin. Metformin HCL may be reinstituted after the acute episode is resolved.

The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either Metformin HCL or sulfonylurea monotherapy, combined therapy with Metformin HCL and sulfonylurea may result in a response. Should secondary failure occur with combined Metformin HCL /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

OverdosageLactic acidosis may occur. Accumulated drug may be removed by haemodialysis.

Special Precautions

Caution when used in patients with CHF especially in those with unstable or acute heart failure. Risk of lactic acid accumulation increases with the degree of renal impairment. May need to discontinue treatment in patients with stress-related states e.g. fever, trauma, infection or surgery. Metformin should be temporarily discontinued for 48 hr in patients undergoing radiologic studies involving intravascular admin of iodinated contrast materials. Elderly. Monitor renal function regularly. May impair ability to drive or operate machinery.

List of Contraindications

Metformin and Pregnancy

Contraindicated in pregnancy

Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Metformin and Lactation

Contraindicated in lactation

Metformin and Children

The safety and effectiveness of Metformin HCL for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of Metformin HCL in this age group is supported by evidence from adequate and well-controlled studies of Metformin HCL in adults with additional data from a controlled clinical study in pediatric patients ages 10-16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults.

Metformin and Geriatic

Controlled clinical studies of Metformin HCL did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Metformin HCL should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Metformin HCL should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Metformin HCL.